Inclusion body beta-thalassemia trait in a Swiss family is caused by an
abnormal hemoglobin (Geneva) with an altered and extended beta chain
carboxy-terminus due to a modification in codon beta 114
P Beris, PA Miescher, JC Diaz-Chico, IS Han, A Kutlar, H Hu, JB Wilson and TH Huisman
Department de Medecine Interne Hopital Cantonal Universitaire de Geneve.
We have analyzed the sequence of the beta globin gene of a chromosome that
is linked to the occurrence of an inclusion body beta-thalassemia
characterized in the heterozygote by moderate anemia, severe red cell
abnormalities, splenomegaly, inclusion body formation, elevated Hb A2
levels, and an increased in vitro alpha/beta chain synthetic ratio. The
data indicate a change in codon 114 from CTG (Leu) to -GG that resulted in
a frameshift and the presumed synthesis of an abnormal beta chain that is
156 residues long with a completely different C-terminal amino acid
sequence. The change in codon 114 gives a -GGGCCC- sequence that creates a
new ApaI site; the resulting 2.6-kilobase fragment has been observed in all
subjects with this thalassemia condition. Protein structural analyses
failed to demonstrate any trace of the abnormal beta chain, even in
reticulocytes and nucleated red cells that were isolated by density
gradient centrifugation. The inclusion bodies appear to contain mainly
normal alpha chains. It is assumed that the structure of the beta-Geneva
chain prevents it from combining with normal alpha chains; this results in
a rapid breakdown of the abnormal protein during the early stages of red
cell maturation and an accumulation of free alpha chains.
Volume 72,
Issue 2,
pp. 801-805,
08/01/1988
Copyright © 1988 by The American Society of Hematology
